T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

项目总结 近年来，癌症免疫治疗取得了长足的进步，但仍需要改进的方法来 在更多的患者中实现更持久的反应。抑制受体的阻断 程序性死亡1(PD-1)使肿瘤反应性T细胞能够有效地识别和消除肿瘤 有反应的患者亚群，但许多患者对PD-1阻断具有抵抗力。为了提高响应率，我们 需要更好地了解导致治疗耐药的机制。这个项目的总体目标是 是为了了解T细胞内在因素在患者反应与抵抗中的作用 PD-1封锁。我们将确定与阻断相关的信号通路和基因表达模式 反应，特别关注T细胞受体(TCR)亲和力的作用。我们假设化妆 肿瘤特异性T细胞TCR亲和力的改变影响肿瘤抗原识别、激活信号和 下游基因表达，从而有助于患者对治疗的反应。对这些参数的分析 在患者样本和小鼠模型中阻断PD-1将使我们能够识别T细胞的特性 对治疗的反应。在我们的第一个目标中，我们将分离和量化黑色素瘤的TCR结合特性 来自PD-1阻断反应和耐药患者的抗原特异性T细胞确定TCR亲和力如何 模型会影响PD-1的阻断反应。在我们的第二个目标中，我们将使用蛋白质组和基因组分析 患者抗原特异性T细胞对PD-1的全球标志性阻断反应和耐药性。在我们的 第三个目的是我们将使用一组黑色素瘤患者来源的TCR，这些TCR对同一抗原具有不同的亲和力 用于体外和体内实验，以确定TCR亲和力如何影响对PD-1阻断的反应。 总体而言，我们将确定黑色素瘤特异性T细胞的TCR亲和力对阻断的贡献 并将提供证据支持基于TCR亲和力的特定T细胞靶向 基于TCR的联合治疗和对PD-1阻断治疗有反应的患者的选择 关联性配置文件。

PROJECT SUMMARY Cancer immunotherapy has made great strides in recent years, yet improved approaches are required to achieve more durable responses in a greater number of patients. Blockade of the inhibitory receptor programmed-death 1 (PD-1) enables tumor-reactive T cells to effectively recognize and eliminate tumors in a subset of responsive patients, but many patients are resistant to PD-1 blockade. To improve response rates, we need to better understand the mechanisms that lead to therapeutic resistance. The overall goal of this project is to understand the role of T cell–intrinsic factors that contribute to patient response versus resistance to PD-1 blockade. We will identify signaling pathways and gene-expression patterns associated with blockade response with a particular focus on the role of T-cell receptor (TCR) affinity. We hypothesize that the make-up of TCR affinities of tumor-specific T cells affects tumor antigen recognition, activation signaling, and downstream gene expression, thus contributing to patient response to therapy. Analysis of these parameters in patient samples and mouse models of PD-1 blockade will allow us to identify T cell properties characteristic of response to therapy. In our first aim we will isolate and quantify the TCR-binding properties of melanoma antigen-specific T cells from PD-1 blockade–responsive and –resistant patients to determine how TCR affinity profiles influence PD-1 blockade responses. In our second aim we will use proteomic and genomic analysis of patient antigen-specific T cells to develop a global signature of PD-1 blockade response and resistance. In our third aim we will use a panel of melanoma patient–derived TCRs with varying affinities for the same antigen for in vitro and in vivo experiments to determine how TCR affinity influences response to PD-1 blockade. Overall, we will determine the contribution of TCR affinities of melanoma-specific T cells to blockade resistance and will provide evidence to support the targeting of specific T cells based on TCR affinity for combination therapies and the selection of patients likely to respond to PD-1 blockade therapy based on TCR affinity profiles.